Sialylation of host proteins as targetable risk factor for COVID‐19 susceptibility and spreading: A hypothesis

Abstract

Individuals infected with the severe acute respiratory syndrome (SARS)‐related coronavirus 2 (SARS‐CoV‐2) develop a critical and even fatal disease, called Coronavirus disease‐19 (COVID‐19), that eventually evolves into acute respiratory distress syndrome. The gravity of the SARS‐CoV‐2 pandemic, the escalating number of confirmed cases around the world, the many unknowns related to the virus mode of action, and the heterogenous outcome of COVID‐19 disease in the population ask for the rapid development of alternative approaches, including repurposing of existing drugs, that may dampen virus infectivity. SARS‐CoV‐2 infects human cells through interaction with sialylated receptors at the surface of epithelial cells, such as angiotensin‐converting enzyme 2 (ACE2). Glycan composition on virus entry receptors has been shown to influence the rate of infection of SARS‐CoV‐2 and spreading of virions has recently been linked to altered lysosomal exocytosis. These processes could concurrently involve the lysosomal system and its glycosidases. We hypothesize that modulating the activity of one of them, the lysosomal sialidase NEU1, could impinge on both the sialylation status of ACE2 and other host receptors as well as the extent of lysosomal exocytosis. Thus NEU1‐controlled pathways may represent therapeutic targets, which could impact on SARS‐CoV‐2 susceptibility, infectivity, and spread.

The role of sialidase Neu1 in respiratory diseases

“…ACE2, as a sialylated glycoprotein, its sialic acids are vital for SARS-CoV-2 infection [ 48 , 49 ]. Reduced NEU1 activity might aggravate SARS-CoV-2 infectious through promoting excessive lysosomal exocytosis in host cells [ 50 ], but this hypothesis needs more clinical and basic evidences to support. In addition, some patients recovered from COVID-19 didn’t produce detectable neutralizing antibodies [ 51 ], whether this phenotype is associated the immune dysfunction caused by NEU1 deficiency in cellular response, we should learn it more accurately and deeply.…”

A novel insight into the nature of modified low-density lipoproteins and their role in atherosclerosis

“…Desialylation and sialylation are essential parts of sialic acid metabolism [128] . However, desialylation is often associated with pathological processes such as sporadic prion disease, infectious diseases, and atherosclerosis [123,129,130] . Desialylation affects endothelial permeability in atherosclerosis.…”

NEU1—A Unique Therapeutic Target for Alzheimer’s Disease

“…An enormous amount of research has been done in recent years exploring the role of Neu1 in numerous cellular mechanisms, and more substrates of NEU1 are being reported over time. Interestingly, some researchers have also found a role for NEU1 in the infection caused by the SARS-CoV-2 virus ( Bongiovanni et al, 2021 ). From the discussion in this paper, it is clear that NEU1 plays a key role in a variety of cellular mechanisms, many of which are directly or indirectly associated with neurogenerative pathologies in rare diseases like sialidosis and also have been linked to highly prevalent neurodegenerative diseases like AD.…”